This invention relates to compositions and methods useful for potentiating the activity of drugs affecting the Central Nervous System.
The following is a list of references which may be important in understanding the background of the invention:
1. U.S. Pat. No 5,942,241;
2. Mancusi L. et al., Minerva Anestesiol, 53(1-2) 19-26, 1987;
3. Huang KS et al., Ma Tsui Hsueh Tsa Chi, 31(4), 245-8, 1993;
4. Goyagi T et al., Anesth Analg. 81(3), 508-13, 1995;
5. Niemi G et al., Acta Anaesthesiol Scand, 42(8), 897-909, 1998;
6. Russian Patent No. SU 2,088,233
7. 8th Sardinian Conference on Neuroscience. Anxiety and depression neurobiology pharmacology; and clinic. Tanka Village, Villasimius, May 24-28th 1995. Behavioral Pharmacology, Vol. 6 (Supplement 1), 1995, P.152.
The references are referred to in the specification by their respective numbers.
Currently, two principal methods of potentiation of the effect of central nervous system (CNS) active drugs (potentiated synergism) are known: (1) pharmacokinetic; and (2) pharmacodynamic.
The pharmacokinetic method provides potentiation by creating a maximum concentration of the drug at the site of the primary pharmacological response due to improved absorption, increased bioavailability, accelerated distribution and retarded elimination of the drug (Goodman and Gilman""s The Pharmacological Basis of Therapeutics 9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996). The known methods of pharmacokinetic potentiation are connected, as a rule, with the development of new and improved dosage forms and ways of drug administration.
In recent years, the method of controlled extended release of active ingredients from micro-particles and microcapsules (e.g. U.S. Pat. No. 6,022,562) has been considered the most popular and promising of these methods. Each micro-particle generally represents a matrix of nontoxic polymer containing a drug and osmotically active polyatomic alcohols (e.g. U.S. Pat. No. 5,431,922). Micro-particles are included in traditional dosage forms for oral administration. (tablets, capsules, suspensions, granules), which most frequently contain polymers such as polyvinylpyrilidone (PVP) or polyethylene oxide (PEO), and osmotically active alcohols such as sorbitol, xylitol and mannitol.
The main drawback of this method is the necessity for permanent administration of a high dose of the active ingredient. This may lead, in the case of long-term administration, to the potentiation not only of its therapeutic action, but also of side effects in case of poor selectivity of the drug effect. In addition, the production of traditional oral dosage forms on the basis of micro-particles and microcapsules leads to a manifold increase in their cost, which often greatly exceeds the cost of the active ingredient. Despite its numerous advantages the aforementioned pharmacokinetic method does not achieve a manifold intensification of the effect of drugs.
Osmotically active polymers (PVP, PEO) and polyatomic alcohols (xylitol, sorbitol, mannitol), included in the composition of both traditional monolithic dosage forms as well as forms intended for controlled release of active ingredients, play an important role in pharmacokinetic potentiation of CNS active drugs (e.g. U.S. Pat. Nos. 4,952,402 and 5,552,429). However, they are not active components of the compositions but rather they only provide optimal conditions for the pharmacokinetics of a CNS active drug.
A combined application of the xcex1-1-adrenomimetics phenylephrine or midodrine, as well as the nonselective adrenomimetic adrenaline together with narcotic analgesics and local anesthetics has been found to lead to a pharmacokinetic potentiation of analgesic and anesthetic effect. However, these compositions were only administered locally to intensify local anesthesia (1) or intrathecally to intensify spinal anesthesia (2-5). intensification and prolongation of the effect of analgesics and anesthetics was caused by an increase in their local concentration, which is due to a decrease in the amount of analgesics and anesthetics entering the blood as a result of a local spasm of vessels caused by the adrenomimetics.
The pharmacodynamic method also provides potentiation by a joint administration of active ingredients causing unidirectional pharmacological effects, but affecting different molecular substrates (having different mechanisms) (Goodman and Gilman""s The Pharmacological Basis of Therapeutics, op. cit.)
Two main types of pharmacodynamic methods of the potentiation of CNS active drugs are known:
(1) Potentiation of the effects of CNS active drugs caused by joint administration of CNS active drugs only;
(2) Potentiation of the effects of CNS active drugs caused by joint administration of a CNS active drug and a peripherally active drug.
The well-known first method consists in joint administration of two CNS active drugs that act unidirectional and mutually potentate each other""s effect. In cases of grave depressions, pain syndrome, parkinsonism, epilepsy and psychoses, potentiation of the maximal effect of antidepressants, neuroleptics, analgesics, psychostimulants, anti-parkinson and anticonvulsive agents is required. As a rule, potentiation is possible only by joint administration of CNS active drugs in submaximal doses. Potentiating of submaximal doses effects of CNS active drugs results in maximum possible intensification of their therapeutic activity On the other hand potentiating of their central toxic effect is also caused resulting in multiple side effects and complications. (e.g. U.S. Pat. No. 4788189; Winter J. C. et al., Pharmacol Biochem Behav, 63(3). 507-13, 1999; Sills T S et al., Behav Pharmacol, 11(2), 109-16, 2000); Fredriksson A. et al., J Neural Transm Cen Sect, 97(3), 197-209, 1994).
U.S. Pat. No. 3,947,579 discloses a method for potentiating the neuroleptic activity of drugs such as butyrophenone derivatives by administrating them together with an amino acid known to cross the blood brain barrier and have muscle relaxant properties useful in the treatment of spinal origin spasticity.
At mild and moderate severity (or stage) of a disease, maximal or even submaximal effect caused by CNS active drug is quite sufficient. In this case therapeutic activity may usually be achieved by potentiating threshold doses of CNS active drugs. (e.g. U.S. Pat. No. 5,891,842; Freedman G. M., Mt. Sinai J Med, 62(3), 221-5, 1995; Kaminsky R et al., Pharmacol Res, 37(5), 375-81, 1998). The potentiation of the effect of threshold doses significantly reduces the probability of the development of side effects and complications inherent to CNS active drugs at maximal doses, as well as the development of tolerance and dependence due to their prolonged administration. However, even this, the safest of all known methods of pharmacodynamic potentiation has its own drawbacks:
1) The effect achieved by potentiating low doses of drugs does not exceed, as a rule, the maximal effect of the drug itself
2) When the elimination of active ingredients is decelerated (childhood age, diseases of liver or kidneys) or the permeability of the hematoencephalic barrier is increased, threshold dosages of CNS active drugs can become submaximal and even toxic in their effect. Therefore, their combined administration even at such threshold doses becomes impossible due to the potentiation of their CNS side effects.
3) The risk of potentiating not only therapeutic, but also toxic effects of CNS active drugs by even small doses of other safe CNS active drugs.
The potentiation of the effects of threshold doses of CNS active drugs can also be realized by a combined administration of a CNS active and a peripherally osmotically active drug. It is known that oral or intramuscular administration of osmotically active copolymers of N-vinyl-pyrrolidone with N,N,N,N, triethylmethacryloidoxyethylammonium iodide (6), which do not penetrate the Blood Brain Barrier, potentiate the effects of threshold doses of analgesics, antidepressant, antishock and antihypoxic agents without any side effects and complications. This is due to stimulation of gastric vagus afferents. Among the drawbacks of the method there should be mentioned the insufficient potentiation of the CNS active drugs when administered at threshold doses. Although potentiation occurs, it does not reach the level of the maximal effect of the CNS drug tested.
Another drawback is the complexity of the synthesis and high cost of the polymers comprised in these compositions.
In rats under urethan anesthesia, peripherally administered serotonin. produced cardiopulmonary reflex. Administration of phenylephrine or adrenaline to anaesthesized rats potentiated 5-10 fold the cardiopulmonary reflex caused by injection of serotonin in short-sleeping rats (7). This is a peripheral rather than a CNS effect, since peripherally administered serotonin cannot penetrate the hematoencephalic barrier.
U.S. Pat. No. 4,631,284 discloses acetaminophen compositions containing a substantially high amount of acetaminophen and a low amount of pheniramine maleate. This patent teaches a method of tabletting using such. compositions.
It is an object of the invention to provide a pharmaceutical composition comprising a CNS active drug whose activity is potentiated.
It is a further object of the invention to provide a method for potentiating CNS active drugs.
In a first aspect of the invention, there is provided a pharmaceutical composition for systemic administration comprising: (a) an effective dose of a drug which affects the central nervous system (CNS); (b) a compound which affects peripheral chemoreceptors; and (c) a stimulator of osmoreceptors.
It has suprisingly been found that the activity of systemically administered CNS drugs may be significantly potentiated by the co-administration of a compound which affects peripheral chemoreceptors and a stimulator of osmoreceptors. The xe2x80x9cactive ingredientsxe2x80x9d of the invention are the CNS drug and the potentiating element, i.e. compound which effects peripheral chemoreceptors and a stimulator of osmoreceptors.
In the present specification, a CNS active drug is a drug that modifies the function of the CNS by directly affecting the CNS or a portion thereof Such drugs include but are not limited to analgesics, antidepressants, neuroleptics, tranquilizers, psychostimulants, hypnotic drugs, anti-parkinson and anti-convulsive agents.
Examples of types of compounds which affect peripheral chemoreceptors are xcex1-1-adrenomimetics and catecholamines. Non-limiting examples of xcex1-1-adrenomimetics are the compounds phenylephrine and midodrine Non-limiting examples of catecholamines are epinephrine, norepinephrine, dopamine, serotonin amid their combination.
Non limiting examples of stimulators of osmoreceptors include PVP, dextran PEO, xylitol, mannitol, sorbitol, or a combination of two or more stimulators.
The term xe2x80x9ceffective dosexe2x80x9d with respect to the CNS drug refers to an amount of the drug which is effective in bringing about a desired effect in the CNS. This amount may be within the usual dosage range of the drug, or it may be less than the usual dosage range of the drug, due to the potentiating effect(s) of the additional components of the composition.
The composition of the invention is systemically administered to the subject (patient). Techniques of administration include systemic parenteral (e.g. intravenous, intramuscular, subcutaneous, inhalation) and systemic enteral (e.g. oral, sublingual, rectal) administration.
In a second aspect of the invention, there is provided a pharmaceutical composition for systemic administration comprising: (a) an effective dose of a drug which affects the central nervous system (CNS); and (b) a compound which affects peripheral chemoreceptors; wherein the dose of the drug in the composition is less than tile usual dose of the drug.
In this aspect of the invention, the xe2x80x9ceffective dosexe2x80x9d of the drug is less the usual, conventional dosage range of the drug. The usual dose of a CNS drug may be ascertained by reference to standard drug and pharmacological handbooks, such as Goodman and Gilman""s The Pharmacological Basis of Therapeutics 9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996, the Physician""s Desk Reference, the Israel Drug Index, or drug product inserts provided by the drug manufacturer. This information is well known and available to the average skilled man of the art.
In the present invention, the term xe2x80x9ccompositionxe2x80x9d may be understood in its usual meaning, i.e. a product of mixing or combining the active ingredients, or the term may be understood as meaning that the active ingredients are administered separately but within a period of time which allows them to interact in the body. For example, in the second aspect of the invention, the compound which affects peripheral chemoreceptors and the CNS active drug may be administered either both parenterally or both orally or else one of them parenterally and the other orally. In the first aspect of the invention, the CNS active drug, the compound which affects peripheral chemoreceptors and the stimulator of osmoreceptors may be administered either all enterally or all parenterally, or else one of them parenterally and the other two enterally, or the reverse.
Preferred compositions according to the invention comprise xcex1-1-adrenomimetic and PVP or dextran for intramuscular administration, and xcex1-1-adrenomimetic and xylitol, PVP or dextran for oral administration.
In a third aspect of the invention, there is provided a method of potentiating the activity of a drug which affects the CNS comprising systemically administrating to a subject the drug together with an effective amount of a compound which affects peripheral chemoreceptors and, optionally, with an effective amount of a stimulator of osmoreceptors.
An xe2x80x9ceffective amountxe2x80x9d of a compound which affects peripheral chemoreceptors or a stimulator of osmoreceptors as used in the method of the invention is an amount which results in a significant decrease of a minimal effective dose of the CNS drug administered together with these components. For example, the effective amount of a peripherical chemoreceptor stimulating component administered together with a CNS active drug may decrease by 10-100 fold the minimal effective dose of a CNS active drug required in order to elicit a maximal therapeutic effect (i.e. potentiates the effect of the CNS active drug threshold dose to give the effect of a maximal dose). The effective amount may also be an amount that potentiates the magnitude of the maximal effect of the CNS drug. Including the osmoreceptor stimulator into the composition results in a substantial additional decrease in the effective dose of the CNS active drug.
Preferred concentration ranges (in weight %) of the active ingredients in a composition according to the invention for systemic parenteral administration are as follows: for the CNS active drug: from 0.0005% to the upper limit of the usual dose for each drug: for xcex1-1-adrenomimetic: from 0.0005% to 0.04%, and for stimulants of osmoreceptors from 0.1% to 10%. Compositions for oral administration preferably comprise each active ingredient in the amount of 0.0001% to 10% of the total weight of the composition. The remaining weight of the composition may comprise standard excipients.
In a fourth aspect of the invention, there is provided a method of treating a disease affecting the CNS comprising systemically administrating to a subject an effective dose of a drug which affects the CNS together with an effective amount of a compound which affects peripheral chemoreceptors and an effective amount of a stimulator of osmoreceptors.
In a fifth aspect of the invention, there is provided a method of treating a disease affecting the CNS comprising systemically administrating to a subject an effective dose of a drug which affects the CNS together with an. effective amount of a compound which affects peripheral chemoreceptors, wherein the dose of the drug in the composition is less than the usual dose of the drug.
In a sixth aspect of the invention, there is provided a method for preparing a pharmaceutical composition for systemic administration of a drug which affects the CNS, said method comprising adding to an effective dose of said drug a compound which affects peripheral chemoreceptors; and a stimulator of osmoreceptors.